Article Text

Safety and efficacy of aceneuramic acid in GNE myopathy: open-label extension study
  1. Naoki Suzuki1,
  2. Madoka Mori-Yoshimura2,
  3. Masahisa Katsuno3,4,
  4. Masanori P Takahashi5,
  5. Satoshi Yamashita6,
  6. Yasushi Oya2,
  7. Atsushi Hashizume3,4,
  8. Shinichiro Yamada3,
  9. Masayuki Nakamori5,
  10. Rumiko Izumi1,
  11. Masaaki Kato1,
  12. Hitoshi Warita1,
  13. Maki Tateyama1,
  14. Hiroshi Kuroda1,
  15. Ryuta Asada7,
  16. Takuhiro Yamaguchi8,
  17. Ichizo Nishino9,
  18. Masashi Aoki1
  1. 1Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan
  2. 2Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan
  3. 3Department of Neurology, Nagoya University Hospital, Nagoya, Japan
  4. 4Department of Clinical Research Education, Nagoya University Graduate School of Medicine, Nagoya, Japan
  5. 5Department of Neurology, Osaka University Hospital, Osaka, Japan
  6. 6Department of Neurology, Kumamoto University Hospital, Kumamoto, Japan
  7. 7Innovative and Clinical Research Promotion Center, Gifu University Hospital, Gifu, Japan
  8. 8Division of Biostatistics, Tohoku University Graduate School of Medicine, Sendai, Japan
  9. 9Department of Neuromuscular Research and Department of Genome Medicine Development, Medical Genome Center, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan
  1. Correspondence to Professor Masashi Aoki, Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan; aokim{at}

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GNE myopathy is a hereditary muscle disorder characterised by a gradually progressive decrease in muscle strength, starting from the distal parts of the arms and legs.1 Patients with GNE myopathy have mutations in the GNE gene encoding a bifunctional enzyme involved in sialic acid (SA) biosynthesis.2 GNE mutations decrease SA production, leading to hyposialylation and eventually to disease onset. In previous clinical studies in Japan, we demonstrated the safety and efficacy of 48-week administration of SA extended-release (SA-ER) tablets in patients with GNE myopathy.3 4 Here, we evaluate the safety and efficacy of long-term SA-ER treatment in an open-label extension study.


Study design, participants and procedures

As an extension of the previous 48-week phase II/III study (hereinafter ‘P2/3 study’),3 we conducted a multicentre, uncontrolled, open-label study in Japan, with a 72-week treatment period followed by a 4-week safety follow-up period. Patients who completed the treatment period in the P2/3 study were eligible for inclusion in the extension study. The SA-ER group and placebo group in the P2/3 study both underwent treatment with SA-ER and were termed the SA-ER/SA-ER group and placebo/SA-ER group, respectively.

Outcome measures


The safety assessments included adverse events (AEs) and clinically meaningful changes in medical history in the intervisit periods, physical examinations, vital signs, clinical laboratory tests, suicidal ideation and related behaviours and concomitant therapies. All AEs that occurred from the time of consent acquisition to 4 weeks after the last study treatment (or the early termination visit) were recorded.


The efficacy of SA-ER was assessed every 24 weeks over the 72-week treatment period in the full analysis set (FAS). The primary efficacy endpoint was the change in the upper extremity composite (UEC) total score from the start of administration of SA-ER in the P2/3 study to the final evaluation time point (or the early termination visit) in the extension study (the entire period).

Additional details on the procedures and analysis methods are provided in online supplemental materials.

Supplemental material


Baseline characteristics and disposition of subjects

A total of 19 subjects were registered in this extension study (SA-ER: 15 and placebo: 4, in the P2/3 study) and all were included in the FAS and safety population (SP). Of the 19 subjects, 18 completed the study, whereas one subject withdrew from the study at the subject’s request. Further details are provided in online supplemental table S1 and figure S1.

Safety assessment

AEs were reported in 15 of 19 subjects in SP. One serious AE of a large intestinal polypectomy reported was considered unrelated to the study drug. There were no AEs leading to discontinuation or withdrawal of the study drug (online supplemental table S2). The most common AEs were viral upper respiratory tract infection (36.8% (7/19 subjects)), fall (31.6% (6/19)) and contusion (21.1% (4/19)) (online supplemental table S3). There were no AEs assessed as severe (grade 3 or higher) in severity and eight AEs were assessed as moderate (grade 2). Five AEs in four subjects (faeces soft (two events); constipation, protein urine present and urine ketone body present (each one event)) were assessed to be related to the study drug (Adverse Drug Reactions (ADRs); online supplemental table S4). All ADRs were mild (grade 1) and resolved and/or recovered by 4 weeks after the last study treatment. No deaths and no clinically meaningful changes in any of the clinical laboratory parameters, weight or vital signs were reported during the extension period.

Efficacy evaluation

In the SA-ER/SA-ER group, the mean change in UEC score from the start of the P2/3 study (Week 0) was −0.08 kg at the end of the 48-week treatment in the P2/3 study (Week 48) and −3.48 kg at the final evaluation in the extension study (Week 120) (figure 1). The mean change in UEC score in the placebo/SA-ER group from Week 0 was −5.33 kg at Week 48 and −8.10 kg at Week 120. Although the difference in the changes in the UEC score at Week 120 between the two groups was not statistically significant by t-test (p=0.1324), a numerical difference was noted between them. The results of other efficacy endpoints are provided in online supplemental materials (figures S2–S9).

Figure 1

Mean change in UEC total score from the start of the P2/3 study (Week 0) to the final evaluation time point (Week 120) of the extension study (FAS). At Week 48, patients completed the previous study and started to receive treatment in the extension study. Vertical lines represent SE. Closed circle and solid line, SA-ER/SA-ER group; open circle and dashed line, placebo/SA-ER group. FAS, full analysis set; SA-ER, sialic acid extended-release; UEC, upper extremity strength composite.


In terms of the safety of the SA-ER tablet, no severe AEs and no AEs leading to discontinuation or withdrawal of the study drug were observed. As ADRs, two events of faeces being soft in two subjects and one event of constipation, proteinuria and ketogenic urine were reported; constipation was also seen in the P2/3 study. None of the ADRs were considered significant safety issues, although caution should be exercised as gastrointestinal disorders such as faeces being soft and constipation may develop. Overall, long-term administration of SA-ER to patients with GNE myopathy was considered well-tolerated and very safe.

The change in UEC score in the SA-ER/SA-ER group as the primary efficacy endpoint was numerically smaller compared with that in the placebo/SA-ER group, indicating that the UEC score in the SA-ER/SA-ER group decreased more slowly in comparison with that in the placebo/SA-ER group during the entire period, which is consistent with the results of our previous studies.3 4 In addition, the present results may imply that initiation of SA-ER treatment at an early phase of the disease is important for delayed disease progression, as suggested by Argov et al.5 Unexpectedly, the UEC score gradually decreased in both the SA-ER/SA-ER and placebo/SA-ER groups during the extension period despite SA-ER administration. The reason for this is currently unknown but should be investigated in the future with a view to improving the effects of SA-ER. Taken together, the present extension study suggests that while long-term treatment with SA-ER was not able to significantly ameliorate GNE myopathy in this group of patients nor completely inhibit disease progression, it may have some beneficial effects in maintaining muscle strength in patients with this condition.

The limitations of the extension study are provided in online supplemental materials.

Ethics statements

Patient consent for publication

Ethics approval

This study involves human participants and was approved by the institutional review board and the ethics committee of Tohoku University Hospital (No. 163007). Participants gave informed consent to participate in the study before taking part.


We are grateful to all the patients and their families who participated in this clinical trial, Registry of Muscular Dystrophy (REMUDY), and Patients Association for Distal Myopathies (PADM). We thank Clinical Research Innovation and Education Center Tohoku University (CRIETO) for their help in scheduling during the study. We also sincerely appreciate the support from Dr. Posner of Columbia University for permitting our free use of the Colombian Suicide Severity Rating Scale in this trial. Medical writing of this paper was supported by Tetsuyoshi Inoue, Ph.D and Mizuko Osaka, Ph.D (SunFlare Co., Ltd., Tokyo, Japan) and the support was funded by Nobelpharma Inc., Ltd.


Supplementary materials

  • Supplementary Data

    This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.


  • Contributors NS, MMY, MK, MPT, SY, IN and MA contributed to the conception and design of the study. YO, AH, SY, MN, RI, MK, HW, MT and HK collected clinical data and patient samples for analysis. RA and TY contributed to conducting the statistical analysis. All the authors contributed to drafting and revising the text, tables and figures.

  • Funding This study was supported by a grant for Research on Rare and Intractable Diseases (H27,28,29-intractable disease) from the Japan Agency for Medical Research and Development (AMED; 16ek0109085h0002, 17ek0109085h0003). The investigational drug used for the trial was provided by Nobelpharma Inc., Ltd., and subsidized by the National Institutes of Biomedical Innovation, Health and Nutrition as an 'Orphan Products Development Support Program'.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.